Alicia Ault

May 25, 2016

WASHINGTON, DC — The immediate and definitive diagnosis of a premature rupture of membranes or miscarriage might be possible if early data on two diagnostic tests pan out.

Both rely on a lateral-flow immunoassay for alpha-fetoprotein embedded in a test strip inside a sanitary pad. One diagnostic uses alpha-fetoprotein to determine whether there has been leakage of amniotic fluid, indicating a premature rupture of membranes. The other uses it to gauge the presence of fetal tissue in vaginal bleeding.

The developer of the diagnostics — Amir Mor, MD, PhD, a third-year resident in obstetrics and gynecology at the Maimonides Medical Center in Brooklyn, New York — said he envisions a day when a pregnant women will be able to use the pads at key times and get real-time information on whether her water has broken or she is having a miscarriage.

Although any hospital can conduct the test at the bedside using this research, Dr Mor and his colleagues have been granted patents that prohibit anyone else from selling the technology. Dr Mor said he has been in discussions with several manufacturers to bring the alpha-fetoprotein-detecting pads to market. "I believe they will be out in less than a year," he told Medscape Medical News.

Hints of the promise of the diagnostic tests were presented in two data-scant posters here at the American Congress of Obstetricians and Gynecologists (ACOG) 2016 Annual Clinical Meeting.

Despite the need for more study of the technology, "the excitement is real," said Nathaniel DeNicola, MD, MSC, an obstetrician–gynecologist at the University of Pennsylvania in Philadelphia.

If a diagnostic could establish rupture of membranes or a failed pregnancy at the point of care, "doctors and patients would both welcome it," Dr DeNicola told Medscape Medical News.

But a single study will not be enough to change practice. It will have to be "verified with repeat studies with more patients," he said.

An Answer in 5 Minutes

In a previous study, Dr Mor's team looked at the effectiveness of alpha-fetoprotein to differentiate amniotic fluid from semen, urine, and vaginal discharge (Obstet Gynecol. 2015;125:448-452).

In the current study, the pads were used by 200 women with confirmed membrane rupture and 70 women with intact membranes.

The diagnostic process is similar to a home pregnancy test. In the case of rupture of membranes, leaking fluid is absorbed by the test strip. If both the control bar and the test bar turn purple in 5 minutes, it is positive for amniotic fluid. The researchers have created a video that shows the technology in action.

All 200 pads used by the women with rupture of membranes tested positive for alpha-fetoprotein, Dr Mor reported. The test was activated in only 36 of the 70 pads used by women with intact membranes. This was expected, he explained, because in half of women with intact membranes, there won't be enough fluid leakage to activate the test. All 36 of these activated tests were negative.

Additional pads were instilled with urine specimens obtained from the 270 women, and 40 pads were instilled with semen collected from an infertility clinic. All these tests were also negative.

Dr Mor reported that he and his colleagues have been using the pads at the bedside with patients who come to their hospital.

Although there are several other tests designed to determine whether amniotic fluid has leaked, none are as sensitive, specific, or as fast and easy as this alpha-fetoprotein diagnostic, Dr Mor said.

One of those tests, the AmniSure, which measures placental alpha-microglobulin, "hasn't been accurate enough to become the gold standard," said Dr DeNicola, who acknowledged that he has never seen it used.

Detecting a Miscarriage

Data on the detection of a failing or failed pregnancy during the first trimester were also presented by Dr Mor. The study won a Blue Ribbon from ACOG reviewers.

The test can identify "whether the pregnancy is inside the uterus or if it's a failing pregnancy," Dr Mor explained.

Those are "very important questions for us when we evaluate a patient" with first-trimester bleeding, he said. It is difficult to know currently — without sending specimens off to pathology — whether fetal tissue is incorporated in that vaginal blood. And determining the disposition of the pregnancy can take a week or more and require several visits.

"The problem here is that I don't have a diagnosis on the first visit," said Dr Mor. The sanitary pad can give a quick answer.

Previous studies have shown that, in the first trimester, alpha-fetoprotein levels are 1000 times higher in fetal blood than in maternal blood, he said.

Seventeen women in the small study were deemed to have a missed or incomplete abortion. Mean alpha-fetoprotein concentration in blood sampled from the vagina was 17,043 ng/mL, and from maternal serum was 116 ng/mL (P < .001). Pathology reports confirmed intrauterine pregnancy in all the specimens.

We need to be assured there are no false negatives.

For the nine women with threatened abortion, mean alpha-fetoprotein concentration in blood sampled from the vagina was 71 ng/mL and from maternal serum was 112 ng/mL (P = .1).

If alpha-fetoprotein was present in vaginal blood at levels at least 8000 times higher than the normal range seen in maternal serum, it confirmed an intrauterine pregnancy that had failed, Dr Mor and his colleagues explain.

For women with confirmed (nonheterotopic) ectopic uterine pregnancy or with cerclage, alpha-fetoprotein concentrations in vaginal blood were similar to concentrations in the maternal serum.

The concept is new and exciting, but "we'd need good evidence that they've distinguished that this is clearly fetal tissue due to a miscarriage," Dr DeNicola said.

The diagnosis is critical, he pointed out. "We need to be assured there are no false negatives."

Dr Mor and Dr DeNicola have disclosed no relevant financial relationships.

American Congress of Obstetricians and Gynecologists (ACOG) 2016 Annual Clinical Meeting: Abstract 25I, presented May 15, 2016; and Abstract 8Q, presented May 16, 2016.


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